Polymers including active agents

ABSTRACT

Polymers are described herein comprising: a reaction product of a prepolymer solution including at least one macromer and at least one visualization agent; and an active agent electrostatically bound to the polymer filament or chemically bound to the at least one monomer; wherein the polymer filament does not include metallic support members.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional patentapplication No. 61/986,015, filed Apr. 29, 2014, the entire disclosureof which is incorporated herein by reference.

FIELD

The present description provides polymers and polymer filaments for theocclusion of vascular sites and cavities within the body, such as theembolization of vascularized tumors or arteriovenous malformationsincluding active pharmaceutical agents that can be released in situ.

SUMMARY

Described herein generally are polymer and/or hydrogel filamentsconfigured to deliver pharmaceutical agents in situ. These polymersand/or hydrogels can also be optionally configured for embolization. Inother embodiments, the polymers and/or hydrogels can be delivered insuch a manner not to substantially occlude flow through a vessel orother lumen.

The polymer filaments can include one or more monomers and/or macromersand a pharmaceutical agent(s) or other active agent(s). The polymer canoptionally include a visualization agent. The pharmaceutical agent canbe entrapped inside the polymers, loaded into the polymers afterpolymerization, or the pharmaceutical agent can be modified to permitpolymerization into the polymers and released over time.

To entrap the pharmaceutical agent in a polymer, the pharmaceuticalagent can be dissolved into a pre-polymerization solution. As thepolymerization of the polymer occurs, the pharmaceutical agent isentrapped by the polymer network. Then, once the polymer filament isdelivered, the pharmaceutical agent can diffuse from the filament.

In another embodiment, when the pharmaceutical agent is loaded into thepolymer after polymerization, a monomer that is capable of binding tothe desired pharmaceutical agent is incorporated into the polymer andformed into a filament. Once the loaded filament is delivered, thepharmaceutical agent can diffuse from the filament.

The pharmaceutical agent itself can also be modified to permitpolymerization into the polymer and release over time from the filament.For example, a polymerizable group with a degradable linkage can beattached to the pharmaceutical agent thereby permitting bothpolymerization into the polymer and subsequent release from thefilament.

In one embodiment, a polymerizable pharmaceutical agent can have astructure

wherein R¹ is a pharmaceutical agent; andp is 0, 1, 2, 3 or 4.

In some embodiments, R¹ is

wherein each R² and R³ can independently be H, CH₃, C₂-C₆ alkyl, C₂-C₆substituted with a halogen or other C₁-C₆ alkyl, NH₂, CO₂, CN, CF₃, F,Cl, Br, I, CCl₃, OH, or CH₂OH;n is 1, 2, 3, or 4;m is 1, 2, 3, or 4;X¹, X², X³, and X⁴ are each N or CH; and

X⁵ is O, CH₂, or NH.

In other embodiments, R¹ is

In still other embodiments, R¹ is

Further still, R¹ can be

Further still, R¹ can be

In one embodiment, a polymerizable pharmaceutical agent can have astructure

In another embodiment, a polymerizable pharmaceutical agent can have astructure

In still another embodiment, a polymerizable pharmaceutical agent canhave a structure

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a graph of gemcitabine eluted over time.

DETAILED DESCRIPTION

Described herein are polymers such as hydrogels formed as filaments orother elongated structures that can contain one or more active agents,pharmaceutical agents, drugs and the like. Herein, active agent,pharmaceutical agent, and drug can be used interchangeably. Thesepolymer filaments can provide controlled release of the pharmaceuticalagent(s) in situ.

In one embodiment, the polymers can include (i) one or more macromersand (ii) one or more pharmaceutical agents. In another embodiment, thepolymers can include (i) one or more monomers, one or more macromers,and/or one or more crosslinkers, and (ii) one or more pharmaceuticalagents. In still another embodiment, the polymers can include (i) one ormore crosslinkers and (ii) one or more pharmaceutical agents.

The polymers can optionally include (iii) one or more visualizationagents. The polymers described can be formed from a prepolymer solution.A particular combination of monomers/macromers/crosslinkers can providediffering polymeric physical properties. Different polymeric physicalproperties can include, but are not limited to tensile strength,elasticity, and/or delivery through a microcatheter or catheter.

The polymers described herein can be provided as filaments or otherelongated structures with round, square, rectangular, triangular,pentagonal, hexagonal, heptagonal, octagonal, ellipsoidal, rhomboidal,torx, or star-shaped cross-sectional shapes. A filament can be describedas having a three dimensional shape such as, but not limited to athread, string, hair, cylinder, fiber, or the like. The filament can beelongated meaning that its length exceeds its width or diameter by atleast 5, 10, 15, 20, 50, 100, 500, 1,000, 10,000, 100,000, 1,000,000,10,000,000, 100,000,000, or more times.

Monomers used to form the herein described polymers can have lowmolecular weights and/or can contain a single polymerizable group. Ifpresent, the monomer(s) can aid in polymerization and impart specificmechanical properties to the resulting polymer filament. The monomerscan be any molecule with a single functionality and conducive to adesired mechanical property.

Specific monomers can include, but are not limited to, t-butylacrylamide, 2-hydroxyethyl methacrylate, hydroxypropyl acrylate,hydroxyl butylacrylate, and derivatives thereof. The hydrophobicity andbulky structure of these specific monomers can impart column strength tothe resulting polymer filament.

In some embodiments, a visualization agent can be a monomer andincorporated into the polymeric structure.

Monomers incorporating visualization characteristics can include one ormore halogen atoms. For example, monomers can include 1, 2, 3, 4, 5, 6,7 or more halogen atoms. In some embodiments, the halogen atoms can beBr or I. In one embodiment, the halogen atoms are I.

In one embodiment, a monomer including a visualization agent or thecharacteristics of a visualization agent can have a structure:

In the above structure, one or more iodine atoms can be replaced bybromine.

In another embodiment, a monomer including a visualization agent or thecharacteristics of a visualization agent can have a structure:

Again, in the above structure, one or more iodine atoms can be replacedby bromine.

In another embodiment, a monomer including a visualization agent or thecharacteristics of a visualization agent can have a structure:

Again, in the above structure, one or more iodine atoms can be replacedby bromine.

Monomers, if present, can be present at a concentration of about 5% w/w,about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30%w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, atleast about 5% w/w, between about 5% w/w and about 40% w/w, betweenabout 10% w/w and about 50% w/w, between about 5% w/w and about 30% w/w,or between about 5% w/w and about 20% w/w, of the prepolymer solution.

Macromers described herein can include large molecular weight compoundssuch as polymers having one or more reactive groups. In someembodiments, macromers with solubility in solvents and functional groupsamenable to modifications may be preferred. Polyethers, due to theirsolubility in a variety of solvents, their availability in a variety offorms, and their available hydroxyl groups, may be preferred macromers.Other macromers can include, but are not limited to, poly(ethyleneglycol), poly(propylene glycol), and poly(tetramethylene oxide).

In other embodiments, a low molecular weight, branched macromer may beused. Such a low molecular weight, branched macromer can include atleast three reactive moieties per molecule so that a high crosslinkdensity of the finalized polymer can be achieved. Example low molecularweight, branched macromers can include ethoxylated pentaerythritolhaving four end groups per molecule, and ethoxylated trimethylolpropanehaving three end groups per molecule.

In still other embodiments, non-polyether polymers with functionalgroups available for modification, such as poly(vinyl alcohol), can alsobe used as macromers.

Macromers can be present at a concentration of about 10% w/w, about 15%w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about40% w/w, about 45% w/w, about 50% w/w, at least about 10% w/w, betweenabout 10% w/w and about 40% w/w, between about 15% w/w and about 25%w/w, between about 15% w/w and about 50% w/w, or between about 15% w/wand about 30% w/w, of the prepolymer solution. In one embodiment, themacromer concentration is about 15% w/w of the prepolymer solution.

The molecular weight of the macromer can alter the mechanical propertiesof the resulting polymer or hydrogel filament. In some embodiments, thealteration of the mechanical properties can be substantial. Smallermolecular weights result in polymers with sufficient column strength tobe pushed through microcatheters and catheters when formed as a filamentor other elongated structures. Larger molecular weights can result inpolymer filaments that can be pushed through microcatheters andcatheters with more difficulty. As such, the macromers described hereincan have a molecular weight of about 50 g/mole, about 100 g/mole, about200 g/mole, about 300 g/mole, about 400 g/mole, about 500 g/mole, about1,000 g/mole, about 1,500 g/mole, about 2,000 g/mole, about 2,500g/mole, about 3,000 g/mole, about 3,500 g/mole, about 4,000 g/mole,about 4,500 g/mole, about 5,000 g/mole, at least about 50 g/mole, atleast about 100 g/mole, between about 50 g/mole and about 5,000 g/mole,between about 100 g/mole and about 5,000 g/mole, between about 1,000g/mole and about 5,000 g/mole, between about 100 g/mole and about 1,000g/mole, or between about 500 g/mole and about 1,000 g/mole. In oneembodiment, the molecular weight is between about 500 g/mole to about1,500 g/mole.

Crosslinkers can also be optionally utilized to impart furthercross-linking of the resulting polymer. The crosslinker can be anymolecule with at least two functionalities to incorporate into theresulting polymer filament. The crosslinker can also be a structureconducive to the desired mechanical property imparted on the finalizedpolymer filament.

Crosslinkers can also be optionally utilized to impart furthercross-linking of the resulting polymer. The crosslinker can be anymolecule with at least two functionalities to incorporate into theresulting polymer filament. The crosslinker can also be a structureconducive to the desired mechanical property imparted on the finalizedpolymer filament.

Crosslinkers can include an ester, a carbonate, a thioester, or acombination thereof. In other embodiments, multiple of each of an ester,a carbonate, a carbamate, an oxalate, and/or a thioester can beincluded.

Other crosslinkers can include N,N-methylenebisacrylamide and ethyleneglycol di methacrylate.

In some embodiments, biodegradable crosslinkers can be used to allow forthe filament to dissolve or otherwise breakdown when placed in vivo orin another appropriate in situ condition.

In one embodiment, a biodegradable crosslinker can have a structure:

In another embodiment, a biodegradable crosslinker can have a structure:

wherein d, e, f, and g are each independently 1-20.

In another embodiment, a biodegradable crosslinker can have a structure:

wherein each n is independently 1-20.

In another embodiment, a biodegradable crosslinker can have a structure:

The crosslinker(s) described herein can have a concentration less thanabout 5% w/w, less than about 4% w/w, less than about 3% w/w, less thanabout 2% w/w, less than about 1% w/w, or less than about 0.5% w/w of theprepolymer solution.

In some embodiments, in order to polymerize themonomers/macromers/crosslinkers, all the components of the polymer havemoieties conducive to a polymerization reaction. A preferredpolymerization mechanism can be free radical polymerization. If freeradical polymerization is utilized to prepare the hydrogel filaments,all components have ethylenically unsaturated moieties. Functionalitiesfor free radical polymerization can include acrylates, methacrylates,vinyl groups, and derivatives thereof. In one embodiment, functionalgroups of the monomers/macromers/crosslinkers are acrylates and/ormethacrylates.

Alternatively, in other embodiments, other reactive chemistries can beutilized for the polymers. Other reactive chemistries can benucleophile/N-hydroxysuccinimide esters, vinyl sulfone/acrylate,thiol-ene, or maleimide/acrylate.

In some embodiments, the polymer can be designed to dissolve in vivo, orbiodegrade. Linkages unstable in the physiological environment, andtherefore biodegradable, can be introduced to the macromer orcrosslinker to impart biodegradation by hydrolytic, oxidative, orreductive mechanisms. Linkages susceptible to breakage in aphysiological environment include those susceptible to hydrolysis,including esters, thioesters, carbamates, oxalates, and carbonates, andthose susceptible to enzymatic action, including peptides that arecleaved by matrix metalloproteinases, collagenases, elastases, andcathepsins.

Multiple crosslinkers can be utilized to control the rate of degradationin a manner that is not possible with only one. In some embodiments, amultiple stage degradation can be achieved with differing crosslinkers.For example, crosslinkers with different degradation rates or modalitiescan be combined to provide a multimodal degradation pattern. A rapidinitial degradation can could be achieved by using a rapid degradingcrosslinker. A second slower degradation can be achieved by using a slowdegrading crosslinker.

Polymer filaments containing pharmaceutical agents can be made to bevisible using medically relevant imaging techniques such as fluoroscopy,computed tomography, or magnetic resonant imaging to permitintravascular delivery and follow-up. Visualization of the polymerfilaments under fluoroscopy can be imparted by incorporating solidparticles of radiopaque materials such as barium, bismuth, tantalum,platinum, gold, and other dense metals into the polymer or bypolymerizing iodine-containing molecules into the polymer filament.Visualization agents for fluoroscopy can include barium sulfate andiodine-containing molecules.

In other embodiments, polymer visualization under computed tomographyimaging can be imparted by incorporation of solid particles of barium orbismuth or by the incorporation of iodine-containing moleculespolymerized into the polymer structure of the filament.

Metals visible under fluoroscopy can sometimes result in beam hardeningartifacts that may preclude the usefulness of computed tomographyimaging for medical purposes.

If used as a visualization agent to render the polymer visible usingfluoroscopic and computed tomography imaging, barium sulfate can bepresent at a concentration of about 20% w/w, about 30% w/w, about 40%w/w, about 50% w/w, about 60% w/w, about 70% w/w, at least about 20%w/w, between about 30% w/w and about 60% w/w, between about 20% w/w andabout 70% w/w, or between about 40% w/w and about 50% w/w of theprepolymer solution.

In some embodiments, the polymer can be visualized using fluoroscopicand computed tomography imaging when it includes about 100 mg, about 125mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500mg, at least about 100 mg, at least about 125 mg, at least about 150 mg,between about 100 mg and about 500 mg, between about 125 mg and about300 mg, or between about 100 mg and about 300 mg of iodine per gram ofpolymer.

Visualization of the filaments under magnetic resonance imaging can beimparted by incorporation of solid particles of superparamagnetic ironoxide or gadolinium molecules polymerized into the polymer structure. Inone embodiment, a preferred visualization agent for magnetic resonanceis superparamagnetic iron oxide. The particle size of the solidparticles can be about 5 μm, about 10 μm, about 15 μm, about 20 μm,about 25 μm, between about 10 μm and about 25 μm, or between about 5 μmand about 15 μm. Concentrations of superparamagnetic iron oxideparticles to render the hydrogel visible using magnetic resonanceimaging range from 0.1% to 1% w/w of the prepolymer solution.

Pharmaceutical agents can be incorporated into the polymer filamentsdescribed herein in many different ways. Pharmaceutical agents can beany compound or drug having a therapeutic effect in an animal such asbut not limited to active agents, drugs, therapeutic agents, and thelike. Pharmaceutical agents can be in an active or inactive form whenintroduced into the filaments or when delivered. Pharmaceutical agentscan include, but are not limited to anti-proliferative compounds,cytostatic compounds, toxic compounds, anti-inflammatory compounds,chemotherapeutic agents, analgesics, antibiotics, protease inhibitors,statins, nucleic acids, polypeptides, growth factors and deliveryvectors including recombinant micro-organisms, liposomes, and the like.

In a first method of incorporation, the pharmaceutical agent(s) can beentrapped in the polymer structure of the polymer filament. In oneembodiment, the pharmaceutical agent is dissolved in the prepolymersolution and then it is entrapped in the network of the polymer as it ispolymerized and formed as a filament. Once the filament is delivered tothe diseased or otherwise desired site, the pharmaceutical agentdiffuses out of the polymer filament. Advantages of this embodiment caninclude simplicity and being able to incorporate a wide variety ofpharmaceutical agents into the polymer filaments. In some embodiments,it may necessary to match the solubility of the polymer components andthe pharmaceutical agent(s).

Secondly, the pharmaceutical agent(s) can be loaded into the polymer. Inthis embodiment, monomers/macromers/crosslinkers are incorporated intothe polymer network that can bind the desired pharmaceutical agent.While any binding mechanism can be used, a preferred binding mechanismis electrostatic interaction. In one embodiment, a monomer with anionizable functional group that is basic (e.g. amines, derivativesthereof, or combinations thereof) can be incorporated into the polymer.The amine group is protonated at pH's less than the pKa of the amine,and deprotonated at pH's greater than the pKa of the amine. Theincorporation of amine groups into the polymer can permit theincorporation of negatively charged pharmaceutical agents throughelectrostatic interaction.

In another embodiment, a monomer with an ionizable functional group thatis acidic (e.g. carboxylic acids, sulfonic acids, phosphoric acids,derivatives thereof, or combinations thereof) can be incorporated intothe polymer network. The acid group is deprotonated at pH's greater thanthe pKa of the acid, and protonated at pH's less than the pKa of theacid. The incorporation of acidic groups into the polymer can permit theincorporation of positively charged pharmaceutical agents throughelectrostatic interaction.

After the preparation and washing of the polymer filament, thepharmaceutical agent is dissolved into a suitable aqueous solvent andthe polymer filament is placed in that solution. The pharmaceuticalagent is loaded into the polymer filament. Once the polymer filament isdelivered to the diseased site, the pharmaceutical agent is released byexchange with other counter ions readily available in the physiologicalenvironment and diffuses out of the polymer filament. The advantages ofthis embodiment include simplicity, the ability to wash the polymerfilament before loading with the pharmaceutical agent, and potentiallyhigher loadings of pharmaceutical agents.

In a third way, the pharmaceutical agent(s) can be incorporated into thepolymer filament. In this embodiment, the pharmaceutical agent ischemically modified to permit incorporation into the network of thefilament and to permit decoupling from the polymer in a controlled rateat the diseased site. The incorporation can be achieved by adding amoiety amenable to the polymerization mechanism selected for thepolymer. The modification turns the pharmaceutical agent into a monomer.The decoupling is achieved by adding a linkage unstable in aphysiological environment between the polymerization group and theactive agent. This linkage can break via hydrolytic, oxidative, orreductive mechanisms available in the physiological environment.Linkages susceptible to breakage in a physiological environment includethose susceptible to hydrolysis, including esters, thioesters,carbamates, oxalates, and carbonates, and those susceptible to enzymaticaction, including peptides that are cleaved by matrixmetalloproteinases, collagenases, elastases, and cathepsins. Multipledecoupling linkages can be used to control the rate of release of thepharmaceutical agent in a manner that is not possible with only one,i.e. one linkage to permit a large, rapid release immediately followingimplantation and another linkage to permit a slow, sustained releaseover longer periods of time. After preparation of polymers withincorporated active agents, extensive washing of the polymers may notprematurely release the pharmaceutical agent. Once the polymer isdelivered to the diseased site, the pharmaceutical agent decouples fromthe polymer as the linkage breaks and diffuses into the diseased site.Advantages of this embodiment include the ability to wash the polymerfilament before loading with pharmaceutical agent, highest loadings ofpharmaceutical agents, complete control of the release kinetics, andsuitability of the widest range of pharmaceutical agents.

In some embodiments, pharmaceutical agents can be polymerizablepharmaceutical agents. In one embodiment, polymerizable pharmaceuticalagents or pharmaceutical agents amenable to polymerization can have astructure

wherein R¹ is a pharmaceutical agent; andp is 0, 1, 2, 3 or 4.

For example, in some embodiments, R¹ can have a structure

wherein each R² and R³ can independently be H, CH₃, C₂-C₆ alkyl, C₂-C₆substituted with a halogen or other C₁-C₆ alkyl, NH₂, CO₂, CN, CF₃, F,Cl, Br, I, CCl₃, OH, or CH₂OH;n is 1, 2, 3, or 4;

-   -   m is 1, 2, 3, or 4;        X¹, X², X³, and X⁴ are each N or CH; and

X⁵ is O, CH₂, or NH.

In another embodiment, R¹ has a structure

In still another embodiment, R¹ has a structure

In one embodiment, R¹ has a structure

In one embodiment, the pharmaceutical agent amenable to polymerizationhas a structure

In another embodiment, a pharmaceutical agent amenable to polymerizationhas a structure

In another embodiment, a pharmaceutical agent amenable to polymerizationhas a structure

In some embodiments, a combination of pharmaceutical agent amenable topolymerization can be used. In such an embodiment, combination of

can be used. Combination ratios can be about 1:99, about 10:90, about20:80, about 30:70, about 40:60, about 50:50, about 60:40, about 70:30,about 80:20, about 90:10, or about 99:1.

In another embodiment, a pharmaceutical agent amenable to polymerizationhas a structure

In another embodiment, a pharmaceutical agent amenable to polymerizationhas a structure

Also, various combinations of the above listed pharmaceutical agents canbe used with filaments as described herein.

Methods of forming the polymer filaments are also described. Methods offorming therapeutic polymer filaments or other elongated structures cancomprise: reacting a prepolymer solution. The prepolymer solution caninclude at least one macromer, at least one visualization agent, and apharmaceutical agent physically entrapped in the polymer filament,electrostatically bound to the polymer filament or chemically bound tothe polymer matrix.

In another embodiment, the prepolymer solution can include (i) one ormore macromers and (ii) one or more pharmaceutical agents. In anotherembodiment, the prepolymer solution can include (i) one or moremonomers, one or more macromers, and/or one or more crosslinkers, and(ii) one or more pharmaceutical agents. In still another embodiment, theprepolymer solution can include (i) one or more crosslinkers and (ii)one or more pharmaceutical agents.

The prepolymer solution can optionally include (iii) one or morevisualization agents. Different combinations ofmonomers/macromers/crosslinkers can provide differing physicalproperties for the resulting polymers. Different polymeric physicalproperties can include, but are not limited to tensile strength,elasticity, and/or delivery through a microcatheter or catheter. Theresulting polymers and/or polymer filaments can include one or morepharmaceutical agents physically entrapped in the polymer filament,electrostatically bound to the polymer filament or chemically bound tothe at least one monomer.

The resulting polymer filament can be prepared for implantation. Afterformation, the polymer filament can be loaded into a support member. Thesupport member can be formed of a metal. In other embodiments, thesupport member is not formed of a metal, but rather formed of a materialsuch as a plastic or other polymer. In other embodiments, the polymerfilaments do not require any support members to be delivered.

For example, to prepare a polymer such as in the shape or form of afilament or other elongated structure, a tubular extrusion is filledwith prepolymer solution. The extrusion is the mold for the filament. Insome embodiments, if one of the components is solid, a solvent will beutilized in the preparation of the filaments. If liquid components areutilized, a solvent may not be required, but may be desired. Any aqueousor organic solvent may be utilized that fully dissolves the desiredmonomers/macromers/crosslinkers, soluble visualization agents,pharmaceutical agents, and polymerization initiators may be used.Solvents can include but are not limited to water, methanol, ethanol,isopropyl alcohol, ether, dimethylformamide, and the like. Solventconcentrations can be about 10% w/w, 20% w/w, 30% w/w, 40% w/w, 50% w/w,60% w/w, 70% w/w, 80% w/w, between about 20% w/w and about 80% w/w,between about 20% w/w and about 50% w/w, or between about 40% w/w andabout 80% w/w. In one embodiment, the solvent is dimethylformamide.

The prepolymer solution can be polymerized by reduction-oxidation,radiation, heat, or any other method known. Radiation cross-linking ofthe prepolymer solution can be achieved with ultraviolet light orvisible light with suitable initiators or ionizing radiation (e.g.electron beam or gamma ray) without initiators. Cross-linking can beachieved by application of heat, either by conventionally heating thesolution using a heat source such as a heating well, or by applicationof infrared light to the monomer or prepolymer solution.

Free radical polymerization of the prepolymer solution in someembodiments is preferred and may require an initiator to start thereaction. In a preferred embodiment, the cross-linking method utilizesazobisisobutyronitrile (AIBN) or another water soluble AIBN derivative(2,2′-azobis(2-methylpropionamidine)dihydrochloride). Other usefulinitiators can include N,N,N′,N′-tetramethylethylenediamine, ammoniumpersulfate, benzoyl peroxides, and combinations thereof, includingazobisisobutyronitriles. Initiator concentrations can be about 1% w/w,about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, between about0.5% w/w and about 5% w/w, between about 1% w/w and about 3% w/w, orbetween about 2% w/w and about 3% w/w. In one embodiment,azobisisobutyronitrile is used as an initiator.

In some embodiments, the prepolymer solution is prepared by placing themonomer/macromer/crosslinker, visualization agent, pharmaceutical agent,and initiator in the solvent. After dissolution of these components, aninsoluble visualization agent, such as barium sulfate orsuperparamagnetic iron oxide particles, can be suspended in theprepolymer solution. In other embodiments, this insoluble visualizationagent is not used. Mixing of the prepolymer solution containing aninsoluble visualization agent with a homogenizer can aid the suspensionof the insoluble visualization agent.

The prepolymer solution can then be injected into tubing with an innerdiameter ranging from 0.015 cm to 0.19 cm and incubated for severalhours at elevated temperature or in boiling water, i.e. 100° C., andsubsequently overnight at 80° C. to complete polymerization. Immersionin boiling water allows for rapid heat transfer from the water to theprepolymer solution contained in the tubing.

The selection of the tubing imparts micro catheter or cathetercompatibility. For delivery through microcatheters, tubing diametersfrom about 0.006 in to about 0.025 in can be used. In one embodiment,the tubing is made from HYTREL® (DuPont, Wilmington, Del.). The HYTREL®tubing can be dissolved in solvents, facilitating removal of a polymerfilament from the tubing.

If the tubing is wrapped around a mandrel prior to polymerization of theprepolymer solution, the resulting hydrogel filament maintains the shapeof the wrapped tubing. Using this wrapping technique, helical, tornado,and complex shapes can be imparted to the finalized filaments. When thetubing is wrapped around a mandrel, the use of oval tubing may bepreferred. After wrapping around the mandrel, the oval shape of thetubing is rounded and the resulting hydrogel filament has a round shapein the coiled configuration.

If HYTREL® tubing is utilized, the hydrogel filament can be recovered byincubating the tubing in a solution of 20% w/w phenol in chloroformfollowed by washing in chloroform and ethanol. After the filament iswashed, it is dried.

Filaments or other elongates structures formed using the present methodscan vary in length depending on the method parameters used. However,generally, filament lengths can range from about 0.5 cm to about 100 cm,about 1 cm to about 50 cm, about 10 cm to about 100 cm, or about 0.5 cmto about 25 cm. Likewise diameters can vary. For example, diameters canbe about 0.010 cm to about 0.50 cm, about 0.015 cm to about 0.19 cm, orabout 0.010 cm to about 0.20 cm.

After recovery and washing of the filament, it is fabricated into adevice suitable for use by a physician, surgeon, or other practitioner.If a repositionable device is desired, a length of filament is insertedinto a tube slightly larger than the filament's diameter. Thisstraightens the secondary shape of the filament and permits the gluingof a poly(ether-ether-ketone) coupler to one end of the filament.Subsequently the coupler is attached to a pusher, packaged, andsterilized.

Upon receipt, the physician introduces the filament into a microcatheteror catheter and then pushes it through the microcatheter or catheter toan embolization or other medically relevant site. The filament can beadvanced and withdrawn until the physician is satisfied with itsposition. Then the filament can be detached from the pusher.

If a pushable device is desired, a dried hydrogel filament is loadedinto an introducer, packaged in a suitable pouch, and sterilized. Uponreceipt, the physician transfers the hydrogel from the introducer to amicrocatheter or catheter using a guide wire or stylet. The driedfilament is then pushed through the microcatheter or catheter and intoan embolization site or other medically relevant site using a guidewire.

Example 1 Preparation of a Hydrogel Filament with EntrappedPharmaceutical Agent

To prepare a hydrogel filament with entrapped active pharmaceuticalagent, 2.25 g of trimethylolpropane triacrylamide, 1.25 g of bariumsulfate and 0.2 g of gemcitabine hydrochloride were added to 2.5 g ofwater. The solution was sparged with argon for 10 min. To initiatepolymerization, 20 μL of tetramethylethylenediamine and 12 μL of a 20%solution of ammonium persulfate in water was added just before injectioninto 0.045 inch ID polyethylene tubing using a 1 cc syringe. The tubingwas heat sealed at both ends and allowed to polymerize overnight at roomtemperature.

Once polymerized, the tubing was cut into 15 cm sections and placed in avacuum oven to remove any residual water. Once dry, the hydrogelfilaments were pushed out of their tubes using a mandrel. Thegemcitabine-containing hydrogel filaments were washed in ethanol for 2hr to remove any unreacted components, then dried overnight in a vacuumoven.

Example 2 Preparation of a Degradable Radiopaque Monomer

To 400 mL of methanol was added 104 g (170 mmol) of diatrizoic acidfollowed by 28 g of cesium carbonate (65 mmol). After stirring for 45min the methanol was removed in vacuo and the solids suspended in 500 mLof diethyl ether. The solids were then collected and dried on a Buchnerfunnel and further dried in vacuo, to yield 120 g, (95%) (CesiumDiatriozate, 1).

To 24 mL of HEMA (200 mmol) in 1,000 mL of dry ether was added 16.8 mL(213 mmol) of pyridine at 4-10° C., under Ar. To this solution was added21.3 mL (200 mmol) of 1-chloroethyl chlorocarbonate, drop wise withstirring over 0.5 hr. After stirring 0.5 hr at 4-10° C., the heavyprecipitate was removed by filtration and the filtrate was concentratedto oil in vacuo, yielding 44 g (100%) (HEMA-1-Chloroethyl carbonate, 2).

To 44 g (200 mmol) of (2) in 400 mL of anhydrous DMF was added 30 g (40mmol) of (1) at 100° C. under Ar, with good stirring. After 15 minanother 40 g (54 mmol) of (1) was added at 100° C., under Ar, with goodstirring followed by a final 30 g (40 mmol), under the same conditions,for a total of 110 g (1) (134 mmol). The reddish brown reaction mixturewas heated at 100° C. for an additional hour and the solvent was removedin vacuo. The reddish brown solid residue was suspended in 1,000 mL ofdry ether and the solids were collected on a Buchner funnel. After thesolids were dried in vacuo, they were suspended in 500 mL distilledwater at 2,000 rpm and the mixture pH was adjusted to 8-9 with cesiumcarbonate. After stirring for 10 min, the suspension was filtered andthe solids were washed 3 times with 100 mL of distilled water, driedovernight in vacuo and crushed to a fine powder. Solid residue was againsuspended in 1,000 mL of dry ether and the solids were collected on aBuchner funnel. After the solids were dried in vacuo again and crushedto a fine powder again, they were purified by silica gel chromatographusing a 1.5 Kg column and a 0-10% gradient of methanol indichloromethane, over 1 hr. This yielded 26 grams (18%), very paleyellow crystalline solid(1-((2-(methacryloyloxy)ethoxy)carbonyloxy)ethyl-3,5-diacetamido-2,4,6-triiodobenzoate,3).

Example 3 Preparation of a Non-Degradable Radiopaque Monomer

Diatriazoyl Acetate (A): To 30.8 g of diatrizoic acid suspended in 100mL of acetic anhydride was added 2 g of concentrated sulfuric acid andthe resulting suspension stirred at 90 degrees centigrade for one hourbefore the reaction mixture was cooled to room temperature and thenpoured onto 500 g of ice. After agitating the ice for 15 min, the oilymass was treated with 100 mL of half saturated sodium bicarbonate whilstagitating. The solids which had formed were collected on a Buchnerfunnel and dried overnight in vacuo to give 9 g of light browndiatriazoyl acetate solids.

Diatriazoyl Chloride (B): Nine grams of ditriazoyl acetate was suspendedin 100 mL of thionyl chloride using overhead stirring. The reactionmixture was brought to reflux in an oil bath and refluxed for one hour.The thionyl chloride was mostly removed in vacuo at 40° C. at whichpoint solids were re-suspended in 100 mL of ethyl acetate which wasremoved in vacuo. This process was repeated twice more at which pointthe solids were placed under vacuum overnight.

Ethylenediamine mono-diatriazoyl amide (C): 6.3 g of the acid chloride(10 mmol) in 300 mL of methylene chloride was added to 6.7 grams ofethylene diamine (100 mmol) over one hour with stirring at 4-10° C.under Ar. The formed solids were collected on a Buchner funnel andwashed with 100 mL of methylene chloride and dried overnight in vacuo.The dried solids now largely free of ethylenediamine were taken up in600 mL of water filtered through a fritted disk funnel and the waterremoved in vacuo. The residue was triturated with acetonitrile which wasthen evaporated in vacuo to remove traces of water. LC-MS showed 640which is (M+Na)⁺ and 656.9, (M+K)⁺.

Ethylene diamine-1-diatriazoylamide-2-methacrylamide (D): To 650 mg of(C) (1 mmol) suspended in 100 mL of THF/CHCl₃/ethanol, 1/3/1 was added0.18 mL (1.04 mmol) of diisopropylethylamine followed by 0.12 mL (1.26mmol) of methacryoyl chloride with stirring under Ar. The reactionmixture was stirred for 1 hr at which point reaction mixture wasfiltered with a fritted Buchner funnel.

TLC with 10% methanol in methylene chloride showed potential product insolids and filtrate. LC-MS of combined filtrate and solids after solventremoval in vacuo showed (M+H)⁺ at 725.0, (M+Na)⁺ at 747.0 as well as(M−H)⁻ at 723.0 and (M+Na−2H)⁻ at 744.9 all on an HPLC peak at 8.9 minin a 15 min run.

Example 4 Preparation of a Degradable Radiopaque Monomer

Tetrabutylammonium diatrizoate: To a stirring suspension of diatrizoicacid (50 g, 81.4 mmol) in methanol (552 mL) was slowly addedtetrabutylammonium hydroxide (40% aqueous solution, 52.8 mL). The turbidsuspension turned clear after the addition of tetrabutylammoniumhydroxide was finished. The solvent was removed using a rotaryevaporator to obtain a cream-colored viscous residue. To this residuewas added appropriate amount of toluene, which was then removed using arotary evaporator. Toluene was added to the residue once more andremoved again. The solid obtained was dried in a vacuum oven overnightat 40° C. to afford a white solid (64.1 g, 92% yield).

Diatrizoyl HEMA: To a stirring solution of KI (796.8 mg, 4.38 mmol) and2-chloro ethylmethacrylate (4.32 mL, 32.1 mmol) in anhydrous DMF (122.6mL) was added tetrabutylammonium diatrizoate (25 g, 29.2 mmol) underargon. The flask was place in a 60° C. oil bath. Additional KI (199 mg)and 2-chloro ethylmethacrylate (1 mL) was added to the reaction at 13hours, 38 hours and 41 hours reaction times. The reaction was pulled outof the oil bath at 44 hours and cooled under room temperature. Thereaction was poured over saturated NaHCO₃ aqueous solution (120 mL) anda white precipitate formed. The aqueous phase was extracted once with amixture of ethyl acetate (280 mL) and methanol (50 mL). The organicphase was washed with saturated sodium chloride aqueous solution (300mL×1). The organic phase was subjected to rotary evaporation to obtain acream-colored wet solid. The solid was suspended in a mixture of methyltert-butyl ether and chloroform (7:3, v/v), and the resulting suspensionwas filtered to obtain a white solid. The solid dried under reducedpressure to obtain the first crop of product as a white solid (11.898g). The previous NaHCO₃ phase was filtered and a white solid wascollected. The solid was washed with a mixture of methyl tert-butylether and chloroform (7:3, v/v) and dried under reduced pressure toafford the second crop (3.071 g). The first and second crops werecombined to afford the final product as a white solid (14.969 g, 70.6%yield).

Example 5 Preparation of a Biodegradable Crosslinker

To 10 g (67.61 mnol) of 2,2′-ethylenedioxy-bis-ethylamine was added 10 g(70.4 mmol) of glycidyl methacrylate and 3.0 g of silica gel (Aldrich645524, 60 Angstrom 200-425 mesh), with good stirring. After stirringfor 1 hr, another 9 g (63.4 mmol) of glycidyl methacrylate was added andthe suspension was stirred for an additional 1.5 hr. The reactionmixture was diluted with 200 mL of reagent grade chloroform and filteredthrough a 600 mL fritted glass Buchner funnel of medium porosity, toremove silica gel. LC-MS analysis of the resultant chloroform solutionshowed almost no mono-glycidyl amino alcohol and mostly bis-glycidylamino alcohol at (M+H)⁺ 433 0.2 and was concentrated to about 50 g invacuo. The resultant heavy syrup was diluted to 100 mL with acetonitrileand stored at −80° C.

Example 6 Preparation of a Biodegradable Crosslinker

TMP-Chloroacetamide (E): To 13.2 g of TMP amine in 250 mL of dry THF wasadded 6.32 g (80 mmol) of pyridine and this solution was added to 6.44 gof chloroacetyl chloride in 250 mL of THF with good stirring, at 4-1° C.under Ar. After stirring for 15 min, the reaction mixture was warmed toroom temperature and the THF and other volatile materials were removedin vacuo. The resulting solids were dissolved into 200 mL of chloroform,washed with 100 mL of saturated aqueous sodium bicarbonate, dried overmagnesium sulfate, and the solvent was removed in vacuo.

TMP-NH-Gly-Methacrylate (F): Approximately 15 grams of (E) was dissolvedinto 75 mL of anhydrous DMF and added 18 g of cesium methacrylate wasadded. The resulting suspension was heated at 40-50° C. for 2 hr.

After precipitation with 500 mL of chloroform, the inorganic salts werecollected by filtration and the filtrate was concentrated in vacuo togive 18 g of a reddish brown oil. This oil was polymerized with AIBN at80° C., in isopropyl alcohol to a nice hard pellet. Chromatography on 6g of this through a plug of silica with 1,200 mL of 2-20% methanol inchloroform, gave 6 g of light red colored material. This material can beused to prepare polymer filaments.

The material can have a structure

wherein d, e, f, and g are each independently 1-20.

Example 7 Preparation of a Biodegradable Crosslinker

Preparation of tetramesyl pentaerythritol (b): To a 3 L three-neck roundbottom flask fitted with a Dean-Stark trap was added pentaerythritol (a,MW˜797 g/mol, 99.9 g, 125 mmol) and toluene (1.5 L) sequentially. Thesolution was subjected to an azeotrope distillation and water wasremoved from the Dean-Stark trap. The flask was cooled to roomtemperature before triethylamine (94.6 mL, 530 mmol) was added. Then theflask was placed in a 0° C. ice bath. A 250 mL addition funnel wasattached to the flask. To the addition funnel was added anhydroustoluene (80 mL) and mesyl chloride (40 mL, 530 mmol) sequentially. Themesyl chloride solution wad added dropwise to the cooled solution. Thereaction was left to stir at room temperature overnight, resulting inthe formation of a white precipitate. At the end of the reaction, thesolution was filtered over a fritted glass funnel to remove theprecipitate. The filtrate was concentrated using a rotary evaporator toafford the crude material as a pale yellow oil (86.37 g).

Preparation of tetraamino pentaerythritol (c): To a solution of ammoniumhydroxide (30%, 1250 mL, 22.02 mol) was added dropwise tetramesylpentaerythriol (b, 86.37 g, 77.8 mmol) in anhydrous acetonitrile (500mL). The reaction was stirred under room temperature for three days.Upon completion, it was degassed for 2 days using an air pump. Then thepH of the residue was adjusted to 14 using 0.1 M NaOH aqueous solution.The aqueous phase was extracted with dichloromethane (500 mL×1, and 1L×1). The organic phase was then dried over sodium sulfate andconcentrated using a rotary evaporator to afford the product as a paleyellow oil (56.31 g).

Preparation of NHS-activated (4-hydroxyphenylmethacrylamide) (e): To asolution of (4-hydroxyphenylmethacrylamide) (d, 20 g, 113 mmol) inanhydrous acetonitrile (78.8 mL) was added anhydrous pyridine (9.12 mL,113 mmol) and disuccinimidyl carbonate (72.4 g, 283 mmol) sequentially.The solution was stirred for 18 hours at room temperature. Then thereaction was poured over dichloromethane (80 mL) and filtered over aBuchner funnel. The filtrate was washed with 2.5% aqueous copper sulfatesolution (100 mL×1), and then saturated sodium chloride solution (100mL×1). It was dried over sodium sulfate and concentrated under reducedpressure. The residue was passed through a short silica gel plug beforebeing separated on flash chromatography using a gradient of ethylacetate and dichloromethane. The product is a cream-colored solid (3.71g, yield: 10.3%).

Preparation of a biodegradable crosslinker (f): To a solution oftetraamino pentaerythritol (c, 10.0 g, 12.6 mmol) and trimethylamine(7.0 mL, 50.4 mmol) in dichloromethane (67 mL) was added NHS-activated(4-hydroxyphenylmethacrylamide) (e, 16.0 g, 50.4 mmol) under argon. Thesolution was stirred for 3 hours 15 minutes. Upon completion, it waspassed through a silica gel plug. The elution was using a rotaryevaporator, and the residue was separated using flash chromatography toafford the product.

Example 8 Preparation of a Biodegradable Crosslinker

To 653 mg (1 mmol) of tetrapeptide Alanine-Proline-Glycine-Leucine(APGL) in 5 mL dry DMF was added 190 mg (1.1 mmol) of APMA-HCl, followedby 174 μL (1 mmol) of DIPEA, at room temperature with good stirring,under Ar. After 2 hr, the reaction mixture was treated with 20 mg of BHTand briefly exposed to air. LC-MS analysis showed (M+H)⁺ at 680 and(M+Na)⁺ at 702. Then, 5 mL of the reaction mixture was added dropwise to200 mL of ether with good stirring and the solids which formed werecollected by centrifugation. The resulting pellet was dissolved into 20mL of (CHCl₃/MeOH/MeOH+5% aqueous ammonia) 90/5/5, and applied to 50 gof silica gel in a 5×20 cm column (Aldrich 645524, 60 Angstrom 200-425mesh). The silica gel column was developed with 500 mL of(CHCl₃/MeOH/MeOH with 5% aqueous ammonia), 90/5/5. The peptidecontaining eluent (TLC, same solvent) was concentrated in vacuo to yield110 mg of pale yellow oil, LCMS, as above. The pale yellow oil wasdissolved in 10 mL of methanol and stored at −80° C.

Example 9 Preparation of a Hydrogel Filament with Loaded PharmaceuticalAgent

A To prepare a filament loaded with a pharmaceutical agent, 1.34 g ofsulfoethyl methacrylate, 0.66 g of the material described in Example 4,0.1 g of pentaerythritol ethoxylate tetra-acrylate, and 0.025 g ofazobisisobutyronitrile were dissolved in 3.4 g of dimethylformamide. Thesolution was sparged with Ar for 10 min before injection into 0.045 inchID HYTREL® tubing using a 1 cc syringe. The tubes were heat sealed atboth ends and placed in a 100° C. water bath for 1 hr, then overnight inan 80° C. oven to polymerize the solution.

The hydrogel was removed by dissolving the tubing in a solution of 20%phenol in chloroform. After the tubing was dissolved, the phenolsolution was exchanged with chloroform and washed for 1 hr. After 1 hr,the chloroform was exchanged and the hydrogel washed for another 1 hr.The chloroform was removed and the hydrogel dried in a vacuum oven for 2hr at 25° C. To remove any unreacted monomers, the hydrogel was placedin ethanol for 12 hr. After 12 hr, the ethanol was exchanged and washedfor 2 hr. After 2 hr, the ethanol was exchanged and the hydrogel washedfor another 2 hr. The ethanol was removed and hydrogel dried in vacuofor 12 hr. The hydrogel filaments were placed in a 10 mg/mL solution ofgemcitabine in water adjusted to pH 4.5 using ammonium hydroxide toload. After 45 min, the filaments were placed in ethanol for 2 hr fordesiccation. The filaments were then placed in a room temperature vacuumoven overnight to remove the ethanol.

Example 10 Preparation of a Polymerizable Pharmaceutical Agent

3′-O-(tert-Butoxycarbonyl)gemcitabine: To 3.0 g (10 mmol) gemcitabine in200 mL of dioxane was added 2.2 g (10 mmol) of di-tert-butyl dicarbonatefollowed by 5.5 g of sodium carbonate and finally 50 mL of water, withgood stirring under Ar. After stirring for 48 hr, the solvent wasremoved in vacuo and the residue distributed between 400 mL water and1,000 mL of ethyl acetate. The aqueous layer was washed with anadditional 500 mL of ethyl acetate, dried with sodium sulfate, and thesolvent was removed in vacuo to give a colorless foam which was mostlyone spot to TLC (50, 40, 10: CH₂Cl₂/acetone/ethanol), R_(f) of about0.4. LC-MS showed (m+1)⁺ of 393.9. Silica gel chromatography on 4×30 cmcolumn with 1:1:0.02-1:1:0.04, CH₂Cl₂/acetone/ethanol gave 2.1 g ofmaterial. The NMR of this compound was the same as previously reported.(Acetone-d6/D₂O).

4-N-3′-O-Bis(tert-Butoxycarbonyl)gemcitabine: To 2.1 g (6 mmol) of3′-O-(tert-butoxycarbonyl)gemcitabine in 200 mL of dioxane was added13.2 grams of di-tert-butyl dicarbonate and the reaction mixture wasplaced in an oven at 37° C. for 72 hr. At the end of this time, thesolvent was removed in vacuo and the residue was placed on the vacuumline at 10 micron for 0.5 hr. The solids which formed were dissolved in40 mL of CHCl₃ and subjected to silica gel chromatography with agradient of CHCl₃ to 10% acetone in CHCl₃, yielding 2.5 g of4-N-3′-O-bis(tert-butoxycarbonyl)gemcitabine material whose NMR(Acetone-d6/D₂O) was consistent with the proposed structure.

5′-O-chloroacyl-4-N-3′-O-Bis(tert-Butoxycarbonyl)Gemcitabine: To 926 mg(2.01 mmol) of 4-N-3′-O-bis(tert-butoxycarbonyl)gemcitabine in 15 mL ofdry THF was added 0.4 mL (2.5 mmol) of diisopropylethyl amine followedby 0.2 mL (2.5 mmol) of chloroacetyl chloride, at −8.0° C. with stirringunder Ar. TLC after 0.5 hour (10% acetone in CHCl₃) indicated a completereaction and at 40 min the reaction mixture was quenched with 20 dropsof isopropyl alcohol and warmed to room temperature. THF was removed invacuo and residue was taken up into 40 mL of CHCl₃ and washed with 10 mLof water, dried with sodium sulfate, and the solvent was removed invacuo to give a foamy semi-solid.

Methacryoyl-5′-O-glycolyl-4-N-3′-O-Bis(tert-butoxycarbonyl)Gemcitabine:Foamy semisolids of5′-O-chloroacyl-4-N-3′-O-bis(tert-butoxycarbonyl)gemcitabine (taken as 2mmol) were taken up into 30 mL of dry DMF and treated with 955 mg (4.3mmol) of cesium methacrylate at 50-80° C. for 4 hr. Solvent was removedin vacuo and brown residual oil was taken up into 150 mL of ethylacetate and washed with portions of saturated aqueous sodiumbicarbonate, dried over sodium sulfate. After solvents were removed, theresidue was subjected to silica gel chromatography with a gradient of2:1 hexane/ethyl acetate to 3:2 hexane/ethyl acetate to give a brownsemi-solid whose NMR (acetone-d6/D₂O) was consistent with the proposedstructure.

2″-methacryoyl-5′-O-glycolyl-Gemcitabine: To 45 mg ofmethacryoyl-5′-O-glycolyl-4-N-3′-O-bis(tert-butoxycarbonyl)gemcitabinein 1.5 mL of dry methylene chloride was added 0.5 mL of trifluoroaceticacid dropwise at 0° C. with stirring under Ar. The reaction mixture wasplaced in a freezer overnight at −4° C. and in the morning the solventwas removed in vacuo. Then, repeated evaporations of 5 mL portions ofmethylene chloride were performed. After treating with several mL oftriethyl amine and evaporating the excess, gradient silica gelchromatography with methylene chloride/acetone: 9/1 to methylenechloride/acetone/ethanol: 5/4/1 gave 35 mg, NMR (acetone-d6/D₂O)consistent with proposed structure of2″-methacryoyl-5′-O-glycolyl-gemcitabine.

Example 11 Preparation of a Polymerizable Pharmaceutical Agent

Preparation of 3′,5′-O-Bis-(tert-butyldimethylsilyl)-gemcitabine: To astirring solution of gemcitabine hydrochloride (12 g, 40 mmol) inanhydrous dimethylformamide (240 mL) was added imidazole (8.17 g, 120mmol) and tert-butyldimethylsilyl chloride (21.1 g, 140 mmol)sequentially. To the resulting solution was added trimethylamine (6.13mL, 44 mmol) dropwise. The solution was stirred under room temperaturefor 15 hours. Then the reaction was filtered over a fritted glassfunnel, and the filtrate was concentrated using a rotary evaporator. Theresidue was suspended in ethyl acetate (200 mL). The organic phase waswashed with saturated sodium bicarbonate solution (200 mL×1) and thensaturated sodium chloride solution (200 mL×1), before being dried oversodium sulfate. The solvent was removed using a rotary evaporator toafford the product as a yellow syrup (22.56 g).

Preparation of3′,5′-O-Bis-(tert-butyldimethylsilyl)-4-N-Boc-gemcitabine: To a solutionof 3′,5′-O-bis-(tert-butyldimethylsilyl)-gemcitabine (3.04 g, 6.18 mmol)in dioxane (24 mL) was added 4-dimethylaminopyridine (105 mg, 0.86mmol), triethylamine (5.2 mL, 37.1 mmol), and Di-tert-butyl dicarbonate(2.13 mL, 9.27 mmol). The reaction was stirred for 24 hours. Uponcompletion, it was poured over 60 mL ethyl acetate and washed with 75 mLsaturated aqueous NaHCO₃ solution. The organic fraction was dried overNa₂SO₄. The crude product (3.87 g) was separated using flashchromatography to afford the product as a clear solid (1.67 g, 45.6%).

Preparation of the 4-N-Boc gemcitabine: To a stirring solution of3′,5′-O-Bis-(tert-butyldimethylsilyl)-4-N-Boc-gemcitabine (7.67 g) inTHF (477 mL) was added tetrabutylammonium fluoride (1 M in THF, 28.6mL). The reaction was stirred for 30 min. Upon completion, the solventwas removed on a rotary evaporator. The reaction was worked up accordingto a published procedure. The crude product was separated on columnusing a gradient of DCM and acetone to afford the product as clearcrystals.

Preparation of carbomethoxymethyl methylacrylate: To a solution of2-bromoacetic acid methyl ester (12.4 mL, 132.4 mmol) in THF (95 mL) at0° C. was added methacrylic acid (9.3 mL, 110.4 mmol) and triethylamine(26.5 mL, 189.9 mmol). The reaction was then pulled out of the ice bathand stirred for 3 hours. Upon completion, a white precipitate wasfiltered off. The filtrate was kept and the solvent was removed on arotary evaporator. The residue was resuspended in 100 mL H₂O, and theaqueous phase was extracted with ethyl acetate (100 mL×2). The combinedorganic fractions were washed with saturated sodium chloride solution(100 mL×1) and dried over Na₂SO₄. The solvent was removed on a rotaryevaporator, and the residue was subjected to distillation to obtain theproduct as a clear liquid with a pleasant aroma (13.97 g, 87.8%).

Preparation of carboxymethyl methacrylate: A solution ofcarbomethoxymethyl methylacrylate (10.85 g, 75.3 mmol) in THF (276.9 mL)and solution of tetramethylammonium hydroxide (2.38%, 276.9 mL) in H₂O(276.9 mL) were mixed and stirred for 3 hours. Then the solution wassubjected to rotary evaporation to remove the THF. An aqueous solutionof HCl (25%, 29 mL) was added to the aqueous phase to adjust the pH toapproximately 3. The aqueous phase was extracted with ethyl acetate (200mL×2). The ethyl acetate fraction was washed with H₂O (200 mL×1) andsaturated NaCl solution (200 mL×1) successively. It was dried overNa₂SO₄ and the solvent was removed on a rotary evaporator. The crystalswere washed with petroleum ether to afford the final product as clearcrystals (9.89 g, 55.8%).

Preparation of 2″-methacryoyl-5′-O-glycolyl-4-N-Boc-Gemcitabine and2″-methacryoyl-3′-O-glycolyl-4-N-Boc-Gemcitabine: To a solution ofcarboxymethyl methacrylate (0.25 g, 1.73 mmol) in DCM (10 mL) was addedN, N′-dicyclohexylcarbodiimide (178.5 mg, 0.865 mmol). After 2 hours ofstirring, a white precipitate was removed over a pad of celite. Thefiltrate was used directly for the next step. To a solution of 4-N-Bocgemcitabine (261.6 mg, 0.72 mmol) in DCM (10.6 mL) was added DMAP (8.8mg, 0.072 mmol) and the filtrate. The reaction was stirred for 18 hours.Upon completion, it was washed with 5 mL saturated aqueous NaHCO₃solution. The organic fraction was dried over Na₂SO₄ and the solvent wasremoved using a rotary evaporator. The crude product was separated usingflash chromatography to obtain the final product as a mixture of the 3′-and 5′-isomers (87.6 mg, 24.8%).

Preparation of 2″-methacryoyl-5′-O-glycolyl-Gemcitabine and2″-methacryoyl-3′-O-glycolyl-Gemcitabine: To a solution of2″-methacryoyl-5′-O-glycolyl-4-N-Boc-Gemcitabine (87 mg, 0.178 mmol) inDCM (0.89 mL) was added trifluoroacetic acid (0.89 mL) at 0° C. Thesolution was stirred for 3.5 hours. Upon completion, the solvent wasremoved using a rotary evaporator. The residue was resuspended in 5 mLethyl acetate. The organic phase was washed successively with 5% NaHCO₃solution (2.5 mL×2) and saturated NaCl solution (2.5 mL×1). The organicfraction was dried over Na₂SO₄ and the solvent was removed using arotary evaporator. The crude product was separated using flashchromatography to afford the product as clear solids (32.9 mg, 47.5%).

Example 12 Preparation of a Polymerizable Active Pharmaceutical Agent

To 3.9 g (10 mmol) of SN-38 in 500 mL dry THF, at 0° C. was added 1.74mL (10 mmol) of diisopropylethylamine followed by 2.96 g (10 mmol) oftriphosgene (Aldrich) in 100 mL of THF, drop wise over 0.5 hr. After 1hour at 0° C., the reaction mixture was transferred to a rapidly stirredflask containing 1.8 g of N,N′-dimethylethylenediamine (50 mmol) in dryTHF. After 1 hour at room temperature, the solvent was removed from thereaction mixture in vacuo followed by an evaporation of 100 mL of DMF invacuo to remove excess amines. The residue was placed on the vacuum lineovernight.

The next day, the residue from the vacuum line was dissolved into 500 mLof THF and 1.74 mL (10 mmol) of diisopropylethyl amine was added. Aftercooling the reaction mixture down to 0° C., 1.1 mL (1.15 mmol) ofmethacryloyl chloride was added in 100 mL of dry THF over 0.5 hour.After 1 hr of stirring at 0° C., the solvent was removed from thereaction mixture and the residue was flashed with 0-5% isopropyl alcoholin methylene chloride, to give the desired MA-bis-carbamate-SN-38product.

Example 13 Preparation of a Polymerizable Active Pharmaceutical Agent

To a 50 mL water suspension of 2.5 g oxaliplatin a (6.30 mmol) beingstirred for 10 minutes at 50° C., 125 mL of 30% H₂O₂ (1.22 mol) wasslowly added as stirring at 50° C. continued. After the reaction mixturebecame homogeneous, the reaction was continued for an additional hour.Charcoal was added to deactivate the residual H₂O₂ and the mixture wasstirred at room temperature overnight. Charcoal was removed byfiltration and the water was removed under vacuum to obtain thedihydroxy oxaliplatin, b, which is a white solid. To a 100 mL anhydrousDMSO suspension of 800 mg dihydroxy oxaliplatin, b (1.856 mmol), 20 mLsolution of 288 mg methacrylic anhydride (1.87 mmol) in anhydrous DMSOwas added dropwise. The reaction mixture was stirred overnight at roomtemperature and became homogeneous. The DMSO was concentrated undervacuum at 55° C. till approximately 5 mL of solution was left. Theproduct was precipitated by adding 200 mL of ether into the crudesolution and stirring overnight. The solid was then collected viafiltration and dried under vacuum for 8 hours. A total of 1.06 g ofmonohydroxy monomethacrylate oxaliplatin, c, was obtained withquantitative yield.

Example 14 Preparation of a Hydrogel Filament with Incorporated ActiveAgent

To prepare a hydrogel filament with an incorporated active agent, 0.71 gof the polymerizable active agent prepared in example 8, 0.3 g of thematerial described in Example 4, 0.2 g of TMP lac/gly, and 0.02 g ofazobisisobutyronitrile were dissolved in 1.25 g of dimethylformamide.The solution was sparged with argon for 10 min before injection into0.045 inch ID HYTREL® tubing using a 1 cc syringe. The tubes were heatsealed at both ends and placed in a 100° C. water bath for 1 hr, thenovernight in an 80° C. oven to polymerize the solution.

The hydrogel was removed by swelling the tubing in chloroform allowingthe filament to be peeled from the tube. The hydrogel was washed inisopropanol for 1 hr to remove any unreacted components, then vacuumdried for 72 hr at room temperature to remove any residual alcohol.

Example 15 Preparation of a Hydrogel Filament with Incorporated ActiveAgent

Samples of gemcitabine loaded filaments prepared as described in Example1, Example 7, and Example 10 were placed in 5 mL of saline and incubatedat 37° C. At various time points, the saline was sampled and exchangedwith fresh saline. The amount of gemcitabine in the saline samples wasdetermined by high performance liquid chromatography and illustrated inthe Table below and in FIG. 1.

mg gemcitabine eluted Time Example 1 Example 7 Example 10  1 hr 4.035.07 0.05  2 hr 0.26 1.54 0.01  5 hr 0.05 0.41 0 20 hr 0.02 0.02 0.01 24hr 0 0 0 72 hr 0 0 0.08  7 d 0 0 0.48 13 d 0 0 1.06 15 d 0 0 0.4 17 d 00 0.36 21 d 0 0 0.97 24 d 0 0 0.31 28 d 0 0 1.92 31 d 0 0 0.72 36 d 0 00.58 38 d 0 0 0.14 46 d 0 0 0.71

The results illustrate the potential difference between quick, shortterm release by entrapping or loading the drug into the filament and aslow long term release by incorporating the drug into the hydrogelfilament.

The preceding disclosures are illustrative embodiments. It should beappreciated by those of skill in the art that the devices, techniquesand methods disclosed herein elucidate representative embodiments thatfunction well in the practice of the present disclosure. However, thoseof skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentsthat are disclosed and still obtain a like or similar result withoutdeparting from the spirit and scope of the invention.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained bythe present invention. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of the invention areapproximations, the numerical values set forth in the specific examplesare reported as precisely as possible. Any numerical value, however,inherently contains certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.

The terms “a” and “an” and “the” and similar referents used in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein is merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.”

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is hereindeemed to contain the group as modified thus fulfilling the writtendescription of all Markush groups used in the appended claims.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on those preferred embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects those of ordinary skill in the art toemploy such variations as appropriate, and the inventors intend for theinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the invention so claimed areinherently or expressly described and enabled herein.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above citedreferences and printed publications are herein individually incorporatedby reference in their entirety.

Further, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

We claim:
 1. A polymer filament comprising: a reaction product of aprepolymer solution including at least one macromer and at least onevisualization agent; and a pharmaceutical agent physically entrapped inthe polymer filament, electrostatically bound to the polymer filament,or chemically bound to the polymer filament via a degradable linkage. 2.The polymer filament of claim 1, further comprising at least one monomerselected from t-butyl acrylamide, 2-hydroxyethyl methacrylate, hydroxylpropyl acrylate, hydroxyl butylacrylate, or a combination thereof. 3.The polymer filament of claim 2, wherein the at least one monomer has aconcentration of between about 5% and about 40% w/w of the prepolymersolution.
 4. The polymer filament of claim 1, wherein the at least onemacromer is poly(ethylene glycol), poly(propylene glycol),poly(tetramethylene oxide), ethoxylated pentaerythritol, ethoxylatedtrimethylolpropane, poly(vinyl alcohol), or a combination thereof. 5.The polymer filament of claim 1, wherein the at least one macromer has aconcentration of between about 15% and about 25% w/w of the prepolymersolution.
 6. The polymer filament of claim 1, wherein the at least onemacromer has a molecular weight of between about 100 g/mole and about5,000 g/mole.
 7. The polymer filament of claim 1, further comprising atleast one crosslinker including an ester, a carbonate, a thioester, or acombination thereof.
 8. The polymer filament of claim 1, wherein the atleast one visualization agent is barium, bismuth, tantalum, platinum,gold, iodine-containing molecules, barium sulfate, or a combinationthereof.
 9. The polymer filament of claim 1, wherein the pharmaceuticalagent is entrapped within the polymer filament.
 10. The polymer filamentof claim 1, wherein the pharmaceutical agent is loaded into the polymerfilament.
 11. The polymer filament of claim 1, wherein thepharmaceutical agent is chemically modified to be chemically bound tothe at least one monomer.
 12. The polymer filament of claim 1, whereinthe polymer filament does not include metallic support members.
 13. Thepolymer filament of claim 1, wherein the polymer filament is configuredfor delivery through a catheter.
 14. A method of forming a therapeuticpolymer filament comprising: reacting a prepolymer solution including atleast one macromer, at least one visualization agent, and an activeagent electrostatically bound to the polymer filament or chemicallybound to the at least one monomer to form the therapeutic polymerfilament.
 15. The method of claim 14, further comprising adding the atleast one monomer to the prepolymer solution, wherein the at least onemonomer is t-butyl acrylamide, 2-hydroxyethyl methacrylate, hydroxylpropyl acrylate, hydroxyl butylacrylate, or a combination thereof. 16.The method of claim 14, wherein the at least one monomer has aconcentration of between about 5% and about 40% w/w of the prepolymersolution.
 17. The method of claim 14, wherein the at least one macromeris poly(ethylene glycol), poly(propylene glycol), poly(tetramethyleneoxide), ethoxylated pentaerythritol, ethoxylated trimethylolpropane,poly(vinyl alcohol), or a combination thereof.
 18. The method of claim14, wherein the at least one macromer has a concentration of betweenabout 15% and about 25% w/w of the prepolymer solution or has amolecular weight of between about 100 g/mole and about 5,000 g/mole. 19.The method of claim 14, further comprising adding the at least onecrosslinker to the prepolymer solution, wherein the at least onecrosslinker includes an ester, a carbonate, a thioester, or acombination thereof.
 20. The method of claim 14, wherein the at leastone visualization agent is barium, bismuth, tantalum, platinum, gold,iodine-containing molecules, barium sulfate, or a combination thereof.21. The method of claim 14, wherein the active agent is entrapped withinthe polymer filament or loaded into the polymer filament.
 22. The methodof claim 14, wherein the active agent is chemically bound to the atleast one monomer.
 23. A polymerizable pharmaceutical agent having astructure

wherein R¹ is a pharmaceutical agent; p is 0, 1, 2, 3 or
 4. 24. Thepolymerizable pharmaceutical agent of claim 23, wherein R¹ is

wherein each R² and R³ is H, CH₃, C₂-C₆ alkyl, C₂-C₆ substituted with ahalogen or other C₁-C₆ alkyl, NH₂, CO₂, CN, CF₃, F, Cl, Br, I, CCl₃, OH,or CH₂OH; n is 1, 2, 3, or 4; m is 1, 2, 3, or 4; X¹, X², X³, and X⁴ areeach N or CH; and X⁵ is O, CH₂, or NH.
 25. The polymerizablepharmaceutical agent of claim 23, wherein R¹ is


26. The polymerizable pharmaceutical agent of claim 23, wherein R¹ is


27. The polymerizable pharmaceutical agent of claim 23, wherein R¹ is


28. The polymerizable pharmaceutical agent of claim 23, wherein R¹ is


29. The polymerizable pharmaceutical agent of claim 23 having astructure


30. The polymerizable pharmaceutical agent of claim 23 having astructure


31. The polymerizable pharmaceutical agent of claim 23 having astructure